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1.  Are Time- and Event-based Prospective Memory Comparably Affected in HIV Infection?† 
According to the multi-process theory of prospective memory (ProM), time-based tasks rely more heavily on strategic processes dependent on prefrontal systems than do event-based tasks. Given the prominent frontostriatal pathophysiology of HIV infection, one would expect HIV-infected individuals to demonstrate greater deficits in time-based versus event-based ProM. However, the two prior studies examining this question have produced variable results. We evaluated this hypothesis in 143 individuals with HIV infection and 43 demographically similar seronegative adults (HIV−) who completed the research version of the Memory for Intentions Screening Test, which yields parallel subscales of time- and event-based ProM. Results showed main effects of HIV serostatus and cue type, but no interaction between serostatus and cue. Planned pair-wise comparisons showed a significant effect of HIV on time-based ProM and a trend-level effect on event-based ProM that was driven primarily by the subset of participants with HIV-associated neurocognitive disorders. Nevertheless, time-based ProM was more strongly correlated with measures of executive functions, attention/working memory, and verbal fluency in HIV-infected persons. Although HIV-associated deficits in time- and event-based ProM appear to be of comparable severity, the cognitive architecture of time-based ProM may be more strongly influenced by strategic monitoring and retrieval processes.
doi:10.1093/arclin/acr020
PMCID: PMC3081684  PMID: 21459901
AIDS dementia complex; Episodic memory; Executive functions; Neuropsychological assessment
2.  Methamphetamine Use Parameters Do Not Predict Neuropsychological Impairment in Currently Abstinent Dependent Adults 
Drug and alcohol dependence  2009;106(2-3):154.
Methamphetamine (meth) abuse is increasingly of public health concern and has been associated with neurocognitive dysfunction. Some previous studies have been hampered by background differences between meth users and comparison subjects, as well as unknown HIV and hepatitis C (HCV) status, which can also affect brain functioning. We compared the neurocognitive functioning of 54 meth dependent (METH+) study participants who had been abstinent for an average of 129 days, to that of 46 demographically comparable control subjects (METH-) with similar level of education and reading ability. All participants were free of HIV and HCV infection. The METH+ group exhibited higher rates of neuropsychological impairment in most areas tested. Among meth users, neuropsychologically normal (n=32) and impaired (n=22) subjects did not differ with respect to self-reported age at first use, total years of use, route of consumption, or length of abstinence. Those with motor impairment had significantly greater meth use in the past year, but impairment in cognitive domains was unrelated to meth exposure. The apparent lack of correspondence between substance use parameters and cognitive impairment suggests the need for further study of individual differences in vulnerability to the neurotoxic effects of methamphetamine.
doi:10.1016/j.drugalcdep.2009.08.010
PMCID: PMC2814900  PMID: 19815352
Methamphetamine; Stimulant; Motor impairment; Neuropsychological; Cognitive impairment; Drug exposure; Predictors
3.  Neurobehavioral effects of HIV infection among former plasma donors in rural China 
Journal of neurovirology  2008;14(6):536-549.
The HIV epidemic in China has expanded rapidly in recent years, but little is known about the prevalence and features of HIV Associated Neurocognitive Disorders (HANDs) in this part of the world. We administered a comprehensive Western neuropsychological (NP) test battery to 203 HIV+ and 198 HIV-former plasma donors in the rural area of Anhui province. We found that 26% in the HIV- sample, and 46% in the HIV+ sample were infected with HCV, which can also have CNS effects. To classify NP impairment, we developed demographically corrected test norms based upon individuals free of both infections (N=141). Using a global summary score, NP impairment was found in 34.2% of the HIV mono-infected group and 39.7% of the co-infected group, as compared to 12.7% of the uninfected controls (p<.001). HIV+ participants with AIDS were more likely to be impaired (43%) than non-AIDS individuals (29%, p<.05). Lastly, when all infection groups were combined, participants with NP impairment reported more cognitive complaints (p<.01) and increased dependence in everyday functioning (p=.01). In sum, NP impairment in this large rural Chinese sample was associated with both HIV and HCV infections, and the impairment's prevalence, severity, and pattern were similar to those reported by Western studies. Clinical significance of NP impairment in this population is suggested by the participants’ reports of reduced everyday functioning. These findings indicate that HAND is likely to be an important feature of HIV infection in developing countries, underscoring the need for international efforts to develop CNS relevant treatments.
doi:10.1080/13550280802378880
PMCID: PMC2889205  PMID: 18991068
HIV; HCV; neurocognitive disorders; China
4.  Etravirine in CSF is highly protein bound 
Objectives
Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL).
Methods
Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8–2000 (plasma) and 0.78–200 (CSF) ng/mL.
Results
Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens.
Conclusions
Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.
doi:10.1093/jac/dks517
PMCID: PMC3625433  PMID: 23335197
HIV; antiretroviral therapy; central nervous system; CNS; protein binding; CSF
5.  Risks and predictors of current suicidality in HIV-infected heroin users in treatment in Yunnan, China: A controlled study 
Objective
Suicide is an important public health problem in China. Elsewhere injection drug use and HIV infection have independently been associated with suicidality, but research has often overlooked these high-risk groups in China. We determined the frequency and predictors of suicidal ideas in Chinese, HIV-infected (HIV+) and uninfected (HIV-) heroin injection drug users in treatment (IDUs) and a control sample. We hypothesized that rates of suicidal ideas would be significantly higher among IDUs compared to controls, and highest among HIV+ IDUs.
Method
We assessed suicidal ideas within the past two weeks in HIV+ (N = 204) and HIV- (N = 202) heroin IDUs in methadone treatment in Yunnan, a province at the intersection of the heroin and HIV epidemics, and in demographically matched, uninfected non-drug using controls (N = 201).
Results
Rates of suicidality were higher in IDUs than controls but there was no additive effect of HIV infection (HIV+ IDU 43.1%; HIV- IDU 37.1%; controls 8.5%). Among HIV+ IDUs suicidality was associated most strongly with a combination of prior history of major depression, low perceived social support, and experience of HIV-relevant stress, but not with AIDS diagnosis. Among HIV- IDUs suicidality was associated with prior history of major depressive or alcohol use disorder. Less than 25% of IDUs with suicidality had histories of mood or alcohol use diagnoses.
Conclusion
Because suicidal ideation is frequent in IDUs in China, regardless of HIV status, and is not fully accounted for by past psychiatric history, additional research may be warranted.
doi:10.1097/QAI.0b013e31827ce513
PMCID: PMC3975910  PMID: 23196829
IV drug use; HIV; Depression; Suicide; China
6.  Relationships Among Neurocognitive Status, Medication Adherence Measured by Pharmacy Refill Records, and Virologic Suppression in HIV-infected Persons 
Background
Optimal antiretroviral therapy (ART) effectiveness depends upon medication adherence, which is a complex behavior with many contributing factors including neurocognitive function. Pharmacy refill records offer a promising and practical tool to assess adherence.
Methods
A substudy of the CHARTER (CNS HIV Anti-Retroviral Therapy Effects Research) study was conducted at the Johns Hopkins University (JHU) and the University of Washington (UW). Pharmacy refill records were the primary method to measure ART adherence, indexed to a “sentinel” drug with the highest central nervous system penetration effectiveness score.
Standardized neuromedical, neuropsychological, psychiatric and substance use assessments were performed at enrollment and at 6 months. Regression models were used to determine factors associated with adherence and the relationships between adherence and change in plasma and cerebrospinal fluid HIV RNA concentrations between visits.
Results
Among 80 (33 JHU, 47 UW) participants, the mean adherence score was 86.4% with no difference by site. In the final multivariable model, better neurocognitive function was associated with better adherence, especially among participants who were at JHU, male, and HIV-infected for a longer time-period. Worse performance on working memory tests was associated with worse adherence. Better adherence predicted greater decreases in cerebrospinal fluid HIV RNA between visits.
Conclusion
Poorer global neurocognitive functioning and deficits in working memory were associated with lower adherence defined by a pharmacy refill record measure, suggesting that assessments of cognitive function, and working memory in particular, may identify patients at risk for poor ART adherence who would benefit from adherence support.
doi:10.1097/QAI.0b013e31827ed678
PMCID: PMC3906725  PMID: 23202813
HIV; adherence; cognitive impairment; pharmacy refill records; HAND; CPE
7.  Continued High Prevalence and Adverse Clinical Impact of Human Immunodeficiency Virus–Associated Sensory Neuropathy in the Era of Combination Antiretroviral Therapy 
Archives of neurology  2010;67(5):552-558.
Objective
To provide updated estimates of the prevalence and clinical impact of human immunodeficiency virus−associated sensory neuropathy (HIV-SN) and neuropathic pain due to HIV-SN in the combination antiretroviral therapy (CART) era.
Design
Prospective, cross-sectional analysis. Clinical correlates for HIV-SN and neuropathic pain, including age, exposure to CART, CD4 levels, plasma viral load, hepatitis C virus infection, and alcohol use disorders, were evaluated in univariate and multivariate models.
Setting
Six US academic medical centers.
Patients
One thousand five hundred thirty-nine HIV-infected individuals enrolled in the CNS (Central Nervous System) HIV Anti-Retroviral Therapy Effects Research study.
Main Outcome Measures
The presence of HIV-SN, defined by 1 or more clinical signs (diminished vibration or sharp sensation in the legs and feet; reduced ankle reflexes) in a distal, symmetrical pattern. Neuropathic pain was defined as aching, stabbing, or burning in a similar distribution. The effect on quality of life was assessed with the Medical Outcomes Study HIV Health Survey.
Results
We found HIV-SN in 881 participants. Of these, 38.0% reported neuropathic pain. Neuropathic pain was significantly associated with disability in daily activities, unemployment, and reduced quality of life. Risk factors for HIV-SN after adjustment were advancing age (odds ratio, 2.1 [95%confidence interval, 1.8–2.5] per 10 years), lower CD4 nadir (1.2 [1.1–1.2] per 100-cell decrease), current CART use (1.6 [1.3–2.8]), and past “D-drug” use (specific dideoxynucleoside analogue antiretrovirals) (2.0 [1.3–2.6]). Risk factors for neuropathic pain were past D-drug use and higher CD4 nadir.
Conclusions
Neuropathic pain and HIV-SN remain prevalent, causing substantial disability and reduced quality of life even with successful CART. The clinical correlates of HIV-SN have changed with the evolution of treatment. These findings argue for redoubled efforts to determine HIV-SN pathogenesis and the development of symptomatic and neuroregenerative therapies.
doi:10.1001/archneurol.2010.76
PMCID: PMC3924778  PMID: 20457954
8.  Diagnosing symptomatic HIV-associated neurocognitive disorders: Self-report versus performance-based assessment of everyday functioning 
Background
HIV-associated neurocognitive disorders (HAND) include both “asymptomatic” and “symptomatic” neurocognitive impairment. Asymptomatic diagnoses indicate HAND without demonstrable functional impairment. The present study compares three approaches to assess functional decline: 1) self-report measures only (SR); 2) performance-based measures only (PB); and 3) combining SR and PB measures (SR+PB).
Methods
We assessed 674 HIV-infected research volunteers with a comprehensive neurocognitive battery; 233 met criteria for a HAND diagnosis by having at least mild neurocognitive impairment. Functional decline was measured via SR and PB measures. HAND diagnoses in these 233 cognitively impaired individuals were determined according to published criteria, which allow for both SR and PB methods in establishing functional decline.
Results
The dual-method diagnosed the most symptomatic (53%; 124/233) HAND conditions, compared to either singular method, which were only 59% concordant. Participants classified as functionally-impaired via PB were more likely to be unemployed, more immunosuppressed, and had more hepatitis-C co-infection, whereas those classified via singular SR were more depressed.
Conclusions
Multimodal methods of assessing everyday functioning facilitate detection of symptomatic HAND. PB-based classification was associated with objective functional status (i.e., employment) and important disease-related factors, whereas the typical SR singular classifications may be biased by depressed mood.
doi:10.1017/S135561771100141X
PMCID: PMC3882265  PMID: 22114912
HIV; Cognition; Assessment of Everyday Functioning; Instrumental Activities of Daily Living
9.  Methamphetamine use and neuropsychiatric factors are associated with antiretroviral nonadherence 
AIDS care  2012;24(12):1504-1513.
The present study assesses the impact of methamphetamine (METH) on antiretroviral (ART) adherence among HIV+ persons, as well as examines the contribution of neurocognitive impairment and other neuropsychiatric factors (i.e., major depressive disorder (MDD), Antisocial Personality Disorder (ASPD), and Attention Deficit Disorder (ADHD)) for ART nonadherence. We examined HIV+ persons with DSM-IV-diagnosed lifetime history of METH abuse/dependence (HIV+/METH+; n = 67) as compared to HIV+ participants with no history of METH abuse/dependence (HIV+/METH−; n = 50). Ancillary analyses compared these groups with a small group of HIV+/METH+ persons with current METH abuse/dependence (HIV+/CU METH+; n = 8). Nonadherence was defined as self-report of any skipped ART dose in the last four days. Neurocognitive functioning was assessed with a comprehensive battery, covering seven neuropsychological domains. Lifetime METH diagnosis was associated with higher rates of detectable levels of plasma and CSF HIV RNA. When combing groups (i.e., METH+ and METH− participants), univariate analyses indicated co-occurring ADHD, ASPD, and MDD predicted ART nonadherence (p’s<0.10; not lifetime METH status or neurocognitive impairment). A significant multivariable model including these variables indicated that only MDD uniquely predicted ART nonadherence after controlling for the other variables (p<0.05). Ancillary analyses indicated that current METH users (use within 30 days) were significantly less adherent (50% prevalence of nonadherence) than lifetime METH+ users and HIV+/METH-participants, and that neurocognitive impairment was associated with nonadherence (p’s<0.05). METH use disorders are associated with worse HIV disease outcomes and ART medication nonadherence. Interventions often target substance use behaviors alone to enhance antiretroviral treatment outcomes; however, in addition to targeting substance use behaviors, interventions to improve ART adherence may also need to address coexisting neuropsychiatric factors and cognitive impairment to improve ART medication taking.
doi:10.1080/09540121.2012.672718
PMCID: PMC3466384  PMID: 22530794
HIV/AIDS; Cognition; Medication Adherence; Antiretroviral; Methamphetamine
10.  HIV-infected individuals with co-occurring bipolar disorder evidence poor antiretroviral and psychiatric medication adherence 
AIDS and behavior  2012;16(8):2257-2266.
The contribution of bipolar disorder (BD), a prevalent serious mental illness characterized by impulsivity and mood instability, to antiretroviral (ART) and psychiatric medication adherence among HIV-infected (HIV+) individuals is unknown. We examined medication adherence among 44 HIV+/BD+ persons as compared to 33 demographically- and medically-comparable HIV+/BD− persons. Classification of adherent (≥90%) or non-adherent (<90%) based on proportion of correctly taken doses over 30 days was determined using electronic medication monitoring devices. HIV+/BD+ persons were significantly less likely to be ART adherent (47.7%) as compared to HIV+/BD− (90.9%) persons. Within the HIV+/BD+ group, mean psychiatric medication adherence was significantly worse than ART medication adherence, although there was a significant correlation between ART and psychiatric adherence levels. Importantly, 30-day ART adherence was associated with plasma virologic response among HIV+/BD+ individuals. Given the high overlap of HIV and BD, and the observed medication adherence difficulties for these persons, specialized adherence improvement interventions are needed.
doi:10.1007/s10461-011-0072-2
PMCID: PMC3351543  PMID: 22041931
Medication Adherence; HIV/AIDS; Bipolar Disorder
11.  Aging, Prospective Memory, and Health-Related Quality of Life in HIV Infection 
AIDS and behavior  2012;16(8):2309-2318.
HIV infection and older age are each independently associated with lower health-related quality of life (HRQoL) and deficits in prospective memory (PM), which is a distinct aspect of cognition involving the ability to “remember to remember” to do something at a future occasion. The present study investigated associations between PM and HRQoL in 72 older (≥ 50 years) and 41 younger (≤ 40 years) HIV-infected adults. Self-reported PM complaints predicted HRQoL across the entire sample, but there was a significant interaction between performance-based PM and age group on HRQoL, such that lower time-based PM was associated with lower HRQoL only in the younger cohort. Within the younger group, time-based and self-reported PM significantly predicted mental HRQoL independent of other risk factors (e.g., depression). These findings suggest that PM plays a unique role in HRQoL outcomes among younger persons living with HIV infection and support the examination of other age-related factors (e.g., effective use of compensatory strategies) that may regulate the adverse impact of PM on everyday functioning.
doi:10.1007/s10461-011-0121-x
PMCID: PMC3352996  PMID: 22246512
AIDS Dementia Complex; Aging; Prospective memory; Quality of life; Functional status; Health status
12.  Impact of COMT Val158Met on executive functioning in the context of HIV and methamphetamine 
The catechol-O-methyltransferease (COMT) Val allele has been linked to executive dysfunction among healthy individuals. The nature of this relationship is unknown in the context of HIV infection and/or methamphetamine (METH) dependence, two conditions that can alter dopaminergic system functioning. We sought to determine if the putative relationship between COMT and executive dysfunction could be observed among individuals with and without HIV-infection and/or METH dependence, and to explore the specificity of this relationship by examining other cognitive domains. Utilizing an existing cohort of 229 men with and without HIV infection and/or METH dependence we found that Met/Met carriers within the HIV-only and control groups, displayed better executive functioning compared to Val/Val and Val/Met carriers. However, this effect was attenuated in the METH-only and comorbid (ie, HIV+/METH+) groups. Examination of other neurocognitive domains were not consistent with effects found for executive functioning. Results support the presumed neuroprotective effect of Met/Met genotype on executive functioning among HIV-only and control groups. Among METH-only and comorbid groups, the slower rate of dopamine clearance conferred by the Met/Met genotype may increase the risk of adverse effects of METH, resulting in comparable executive dysfunction to that of Val allele carriers.
doi:10.2147/NBHIV.S8245
PMCID: PMC3782745  PMID: 24078782
Val158Met; Endophenotype; Executive Function
13.  Preliminary Evidence for Feasibility, Use, and Acceptability of Individualized Texting for Adherence Building for Antiretroviral Adherence and Substance Use Assessment among HIV-Infected Methamphetamine Users 
AIDS Research and Treatment  2013;2013:585143.
The feasibility, use, and acceptability of text messages to track methamphetamine use and promote antiretroviral treatment (ART) adherence among HIV-infected methamphetamine users was examined. From an ongoing randomized controlled trial, 30-day text response rates of participants assigned to the intervention (individualized texting for adherence building (iTAB), n = 20) were compared to those in the active comparison condition (n = 9). Both groups received daily texts assessing methamphetamine use, and the iTAB group additionally received personalized daily ART adherence reminder texts. Response rate for methamphetamine use texts was 72.9% with methamphetamine use endorsed 14.7% of the time. Text-derived methamphetamine use data was correlated with data from a structured substance use interview covering the same time period (P < 0.05). The iTAB group responded to 69.0% of adherence reminder texts; among those responses, 81.8% endorsed taking ART medication. Standardized feedback questionnaire responses indicated little difficulty with the texts, satisfaction with the study, and beliefs that future text-based interventions would be helpful. Moreover, most participants believed the intervention reduced methamphetamine use and improved adherence. Qualitative feedback regarding the intervention was positive. Future studies will refine and improve iTAB for optimal acceptability and efficacy. This trial is registered with ClinicalTrials.gov NCT01317277.
doi:10.1155/2013/585143
PMCID: PMC3776360  PMID: 24078868
14.  Preliminary evidence of motor impairment among polysubstance 3,4-methylenedioxymethamphetamine users with intact neuropsychological functioning 
Neuropsychological disturbances have been reported in association with use of the recreational drug “ecstasy,” or 3,4-methylenedioxymethamphetamine (MDMA), but findings have been inconsistent. We performed comprehensive neuropsychological testing examining seven ability domains in 21 MDMA users (MDMA+) and 21 matched control participants (MDMA−). Among MDMA+ participants, median [interquartile range] lifetime MDMA use was 186 [111, 516] doses, with 120 [35–365] days of abstinence. There were no significant group differences in neuropsychological performance, with the exception of the motor speed/dexterity domain in which 43% of MDMA+ were impaired compared with 5% of MDMA− participants (p = .004). Motor impairment differences were not explained by use of other substances and were unrelated to length of abstinence or lifetime number of MDMA doses. Findings provide limited evidence for neuropsychological differences between MDMA+ and MDMA− participants with the exception of motor impairments observed in the MDMA+ group. However, replication of this finding in a larger sample is warranted.
doi:10.1017/S1355617710000846
PMCID: PMC3737074  PMID: 20735886
Ecstasy; N-Methyl-3; 4-methylenedioxyamphetamine; Neurocognitive; Neurotoxicity; Stimulant; Hallucinogen
15.  Health-Related Quality of Life ‘Well-Being’ In HIV Distal Neuropathic Pain Is More Strongly Associated With Depression Severity Than With Pain Intensity 
Psychosomatics  2012;53(4):380-386.
Background
Despite modern antiretroviral treatment, HIV-associated distal neuropathic pain (DNP) remains one of the most prevalent and debilitating complications of HIV disease. Neuropathic pain is often accompanied by depressed mood, and both pain and depression have been associated with decreased health-related quality of life (HRQOL) well-being. The relative contribution of depression and pain to worse life quality has not been addressed, however, even though a better understanding might sharpen intervention strategies.
Methods
We used the Medical Outcomes Study HIV (MOS-HIV) Health Survey and the Beck Depression Inventory-II and linear regression models to investigate HRQOL well-being in HIV-infected patients with DNP (N=397) participating in an observational cohort study at six US sites (CNS HIV Antiretroviral Treatment Effects Research Study, CHARTER).
Results
For this sample of patients with HIV DNP, severity of depressed mood was more highly correlated with HRQOL well-being than was pain intensity.
Conclusions
These results suggest that interventions to improve HRQOL well-being in individuals with HIV-associated DNP may need to address not only pain intensity, but mood state as well.
doi:10.1016/j.psym.2012.05.002
PMCID: PMC3389373  PMID: 22748751
Quality of Life; Depression; HIV-Associated Distal Neuropathic Pain; Pain Intensity
16.  Working Memory Deficits Affect Risky Decision-Making in Methamphetamine Users with Attention-Deficit/Hyperactivity Disorder 
Journal of Psychiatric Research  2012;46(4):492-499.
Methamphetamine (MA) use and Attention-Deficit/Hyperactivity Disorder (ADHD) commonly co-occur and are independently associated with dysregulation of frontostriatal loops and risky decision-making; however, whether their comorbidity exacerbates risky decision-making is not known. This study evaluated 23 participants with histories of MA dependence and ADHD (MA+ADHD+), 25 subjects with MA dependence alone (MA+ADHD−), and 22 healthy adults (MA−ADHD−), who completed the Iowa Gambling Task (IGT) as part of a larger neuropsychiatric research evaluation. Results showed a significant interaction between ADHD, MA, and working memory, such that individuals with working memory deficits in the ADHD+MA+ cohort demonstrated the strongest propensity to select cards from “disadvantageous” versus “advantageous” decks on the IGT. This effect was unique to working memory and was not better explained by other psychiatric, substance use, or neuromedical factors. Findings suggest that working memory deficits may moderate the expression of risky decision-making in MA users with ADHD.
doi:10.1016/j.jpsychires.2012.01.006
PMCID: PMC3307875  PMID: 22305489
Amphetamine; Attention Deficit Disorder with Hyperactivity; Cognitive Processes; Drug Abuse; Short Term Memory; Dysexecutive Syndrome
17.  Sustained Attention Deficits Among HIV-Positive Individuals With Comorbid Bipolar Disorder 
Difficulties with sustained attention have been found among both persons with HIV infection (HIV+) and bipolar disorder (BD). The authors examined sustained attention among 39 HIV+ individuals with BD (HIV+/BD+) and 33 HIV-infected individuals without BD (HIV+/BD−), using the Conners’ Continuous Performance Test–II (CPT–II). A Global Assessment of Functioning (GAF) score was also assigned to each participant as an overall indicator of daily functioning abilities. HIV+/BD+ participants had significantly worse performance on CPT–II omission errors, hit reaction time SE (Hit RT SE), variability of SE, and perseverations than HIV+/BD− participants. When examining CPT–II performance over the six study blocks, both HIV+/BD+ and HIV+/BD− participants evidenced worse performance on scores of commission errors and reaction times as the test progressed. The authors also examined the effect of current mood state (i.e., manic, depressive, euthymic) on CPT–II performance, but no significant differences were observed across the various mood states. HIV+/BD+ participants had significantly worse GAF scores than HIV+/BD− participants, which indicates poorer overall functioning in the dually-affected group; among HIV+/BD+ persons, significant negative correlations were found between GAF scores and CPT–II omission and commission errors, detectability, and perseverations, indicating a possible relationship between decrements in sustained attention and worse daily-functioning outcomes.
doi:10.1176/appi.neuropsych.11010028
PMCID: PMC3575087  PMID: 22450615
18.  Lifetime Suicidal Ideation and Attempt is Common Among HIV+ Individuals 
Journal of Affective Disorders  2011;136(3):993-999.
Background
Estimates of the prevalence of lifetime suicidal ideation and attempt, and risks for new-onset suicidality, among HIV-infected (HIV+) individuals are not widely available in the era of modern combined antiretroviral treatment (cART).
Method
Participants (n=1560) were evaluated with a comprehensive battery of tests that included the depression and substance use modules of the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory-II (BDI-II) as part of a large prospective cohort study at six U.S. academic medical centers. Participants with possible lifetime depression (n=981) were classified into five categories: 1) no thoughts of death or suicide (n=352); 2) thoughts of death (n=224); 3) thoughts of suicide (n=99); 4) made a suicide plan (n=102); and 5) attempted suicide (n=204).
Results
Twenty-six percent (405/1560) of participants reported lifetime suicidal ideation and 13% (204/1560) reported lifetime suicide attempt. Participants who reported suicidal thoughts or plans, or attempted suicide, reported higher scores on the BDI-II (p<0.0001), and higher rates of current major depressive disorder (p=0.01), than those who did not. Attempters reported higher rates of lifetime substance abuse (p=0.02) and current use of psychotropic medications (p=0.01) than non-attempters.
Limitations
Study assessments focused on lifetime, rather than current, suicide. Data was not collected on the timing of ideation or attempt, frequency, or nature of suicide attempt.
Conclusions
High rates of lifetime suicidal ideation and attempt, and the relationship of past report with current depressed mood, suggests that mood disruption is still prevalent in HIV. Findings emphasize the importance of properly diagnosing and treating psychiatric comorbidities among HIV persons in the cART era.
doi:10.1016/j.jad.2011.06.044
PMCID: PMC3222733  PMID: 21784531
HIV; depression; suicide
19.  Cytochrome P450-2D6 extensive metabolizers are more vulnerable to methamphetamine-associated neurocognitive impairment: Preliminary findings 
While neuropsychological deficits are evident among methamphetamine (meth) addicts, they are often unrelated to meth exposure parameters such as lifetime consumption and length of abstinence. The notion that some meth users develop neuropsychological impairments while others with similar drug exposure do not, suggests that there may be individual differences in vulnerability to the neurotoxic effects of meth. One source of differential vulnerability could come from genotypic variability in metabolic clearance of meth, dependent on the activity of cytochrome P450-2D6 (CYP2D6). We compared neuropsychological performance in 52 individuals with a history of meth dependence according with their CYP2D6 phenotype. All were free of HIV or hepatitis C infection and did not meet dependence criteria for other substances. Extensive metabolizers showed worse overall neuropsychological performance and were three times as likely to be cognitively impaired as intermediate/poor metabolizers. Groups did not differ in their demographic or meth use characteristics, nor did they evidence differences in mood disorder or other substance use. This preliminary study is the first to suggest that efficient meth metabolism is associated with worse neurocognitive outcomes in humans, and implicates the products of oxidative metabolism of meth as a possible source of brain injury.
doi:10.1017/S1355617710000779
PMCID: PMC3543816  PMID: 20727252
Substance abuse; CYP2D6; Polymorphisms; Neurotoxicity; Metabolism; Cognition
20.  Neuropsychiatric Aspects of HIV Infection 
Western Journal of Medicine  1989;151(3):313-314.
PMCID: PMC1026869  PMID: 18750639
21.  Neurocognitive Impact of Substance Use in HIV Infection 
BACKGROUND
To determine how serious a confound substance use (SU) might be in studies on HIV-associated neurocognitive disorder (HAND) we examined the relationship of SU history to neurocognitive impairment (NCI) in participants enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study.
METHODS
After excluding cases with behavioral evidence of acute intoxication and histories of factors that independently could account for NCI (e.g., stroke), baseline demographic, medical, SU, and neurocognitive data were analyzed from 399 participants. Potential SU risk for NCI was determined by the following criteria: lifetime SU DSM-IV diagnosis, self-report of marked lifetime SU, or positive urine toxicology (UTOX). Participants were divided into three groups: no SU (N = 134), Non-syndromic SU (N = 131), syndromic SU (N = 134) and matched on literacy level, nadir CD4, and depressive symptoms.
RESULTS
While approximately 50% of the participants were diagnosed with HAND, a MANCOVA of neurocogntive summary scores, covarying for UTOX, revealed no significant effect of SU status. Correlational analyses indicated weak associations between lifetime heroin dosage and poor recall and working memory, as well as between cannabis and cocaine use and better verbal fluency.
CONCLUSIONS
These data indicate that HIV neurocognitive effects are seen at about the same frequency in those with and without historic substance abuse, in cases that are equated on other factors that might contribute to NCI. Therefore, studies on neuroAIDS and its treatment need not exclude such cases. However, the effects of acute SU and current SU disorders on HAND require further study.
doi:10.1097/QAI.0b013e318229ba41
PMCID: PMC3183737  PMID: 21725250
Substance use; HIV-associated neurocognitive disorder; cognition
22.  Approaches to Identifying Appropriate Medication Adherence Assessments for HIV Infected Individuals with Comorbid Bipolar Disorder 
AIDS Patient Care and STDs  2012;26(7):388-394.
Abstract
Assessing medication adherence in already difficult-to-treat HIV-infected subpopulations presents a unique challenge. The objective of this study was to compare different approaches to assessing medication adherence: (1) electronic medication monitoring, (2) standardized self-report questionnaire, and (3) self-report visual analogue scale, and to determine whether antiretroviral therapy (ART) adherence measures differed for HIV-infected persons with bipolar disorder (HIV+ /BD+) as compared to HIV-infected persons without bipolar disorder (HIV+ /BD−). ART adherence was assessed for 74 HIV-positive participants using the Medication Event Monitoring System (MEMS), AIDS Clinical Trials Group (ACTG) adherence questionnaire, and visual analogue scale (VAS). Participants were classified as adherent or nonadherent on each measure by previously validated cutscores. Correlations and logistic regressions were used to examine associations between adherence measures and demographic and clinical variables. In the HIV+ /BD− group, significant correlations existed between each self-report measure and the MEMS. Males comprised 81% of the study population. Participants averaged 44 years of age and 13 years of education. No significant correlations were found among adherence measures in the HIV+ /BD+ group. Among participants reporting adherence on either self-report measure but classified as nonadherent based on MEMS, 94% had a diagnosis of bipolar disorder. Bipolar disorder was a significant predictor of adherence classification discordance among self-report measures. Our findings suggest that it remains difficult to assess ART adherence among HIV-positive individuals with bipolar disorder. Combined approaches of self-report and objective measures may be the best way to estimate adherence, and may provide the best basis for interventions designed to improve adherence in difficult-to-treat populations.
doi:10.1089/apc.2011.0447
PMCID: PMC3961000  PMID: 22686169
23.  Psychiatric Context of Human Immunodeficiency Virus Infection among Former Plasma Donors in Rural China 
Journal of Affective Disorders  2010;130(3):421-428.
Background
China’s HIV epidemic commenced in its agrarian provinces through contaminated commercial plasma donation centers and is now becoming a public health concern nationwide. Little is known of the psychiatric and substance use disorder characteristics of this population, or their impact on everyday function, employment, and life quality.
Methods
HIV infected (HIV+) former plasma donors (N = 203) and HIV-negative (HIV-) donor controls (N = 198) completed the World Mental Health Survey Composite International Diagnostic Interview to determine lifetime major depressive disorder (MDD), substance use disorders, and suicidality. Current mood and suicidality were assessed with the Beck Depression Inventory-II. Everyday function was measured by an Activity of Daily Living questionnaire; life quality was evaluated by the Medical Outcomes Study-HIV.
doi:10.1016/j.jad.2010.10.039
PMCID: PMC3307799  PMID: 21094530
24.  Correlation of major depressive disorder symptoms with FKBP5 but not FKBP4 expression in human immunodeficiency virus–infected individuals 
Journal of Neurovirology  2010;16(5):399-404.
Major depressive disorder (MDD) is a significant cause of morbidity in people living with the human immunodeficiency virus (HIV). FKBP5 is a candidate gene with single-nucleotide polymorphisms (SNPs) rs1360780 and rs3800373 associated with MDD. This gene product and its relative, FKBP4, physically associate with the glucocorticoid receptor whose function is implicated in MDD pathophysiology. Because these genes are expressed in blood and brain and elevated in HIV infection, we explored the relationship between gene expression, genotype, and MDD symptoms. Longitudinally followed subjects (N = 57) as part of the CNS HIV AntiRetroviral Effects Research study, with diagnosed MDD and who donated blood for genotyping and gene expression analysis, were assessed. Subjects donated blood on adjacent visits with and without meeting criteria for MDD episode. Changes in clinical parameters were compared changes in gene expression. Change in FKBP5 expression correlated with change in Beck Depression Inventory (BDI) for MDD → euthymic comparison in GG genotype of rs3800373 (P = .013) and TT carriers of rs1360780 (P = .02). In euthymic → MDD comparison, GG homozygous, FKBP5 expression correlated with more severe change in BDI. Change in FKBP4 expression did not correlate with changes in clinical or depression measurements. Higher FKBP5 expression correlated with greater symptom change for GG carriers of rs3800373.
doi:10.3109/13550284.2010.504248
PMCID: PMC3274491  PMID: 20726698
FKBP4; FKBP5; gene expression; genotyping; HIV; human immunodeficiency virus; major depression; major depressive disorder
25.  Efavirenz concentrations in CSF exceed IC50 for wild-type HIV 
Objectives
HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF.
Methods
CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF).
Results
Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2–17] of therapy were 2145 ng/mL in plasma (IQR 1384–4423) and 13.9 ng/mL in CSF (IQR 4.1–21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026–0.0076; n = 69). The CSF/IC50 ratio was 26 (IQR 8–41) using the published IC50 for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC50 for wild-type HIV.
Conclusions
Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC50 in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.
doi:10.1093/jac/dkq434
PMCID: PMC3019085  PMID: 21098541
CNS; pharmacology; non-nucleoside reverse transcriptase inhibitors

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